Methylecgonidine
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Names | |
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IUPAC name
Methyl (1S,5R)-8-methyl-8-azabicyclo[3.2.1]oct-3-ene-4-carboxylate
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Other names
Anhydromethylecgonine
Anhydroecgonine methyl ester |
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Identifiers | |
43021-26-7 ![]() |
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ChemSpider | 21106453 ![]() |
Jmol 3D model | Interactive image |
PubChem | 119478 |
UNII | 58C337KP3E ![]() |
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Properties | |
C10H15NO2 | |
Molar mass | 181.24 g·mol−1 |
Vapor pressure | {{{value}}} |
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
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Infobox references | |
Methylecgonidine (anhydromethylecgonine; anhydroecgonine methyl ester; AEME) is a chemical intermediate derived from ecgonine or cocaine.
Methylecgonidine is a pyrolysis product formed when crack cocaine is smoked, making this substance a useful biomarker to specifically test for use of crack cocaine, as opposed to powder cocaine which does not form methylecgonidine as a metabolite.[1] Methylecgonidine has a relatively short half-life of 18-21 minutes, after which it is metabolised to ecgonidine, meaning that the relative concentrations of the two compounds can be used to estimate how recently crack cocaine has been smoked. Methylecgonidine has been shown to be specifically more harmful to the body than other byproducts of cocaine; for example to the heart,[2] lungs[3] & liver.[4] The toxicity is due to a partial agonist effect at M1 and M3 muscarinic receptors, leading to DNA fragmentation and neuronal death by apoptosis.[5]
AEME is also used in scientific research for the manufacture of phenyltropane analogues such as Troparil, Dichloropane, Iometopane and CFT. Methylecgonidine could also theoretically be used to produce cocaine and so may be a controlled substance in some countries.
Synthesis
Methylecgonidine can be synthesized from cocaine via hydrolysis,[6] dehydration,[7] and esterification.[8]
The scheme by Kline[9] is based on the reaction of 2,4,6-cycloheptatriene-7-carboxylic acid with methylamine. This is a modified version of U.S. Patent 2,783,235 by Grundmann and Ottmann. In the accompanying patent U.S. Patent 2,783,236 these same authors react their methylecgonidine with two equivalents of PhLi to form a tertiary alcohol by "hard" addition to the ester and not "soft" Michael addition. However, the product is only one tenth the potency of atropine. The methyl 2,4,6-cycloheptatriene-1-carboxylate can be made synthetically.[10][11]
Davies et al. synthesized (R/S)-methylecgonidine by a tandem cyclopropanation/Cope rearrangement.[12][13] Thus, reaction of methyldiazobutenoate (2) with 5 equiv of N-((2-(TMS)ethoxy)carbonyl)pyrrole (1) in the presence of rhodium(II) hexanoate/hexane gave the [3.2.1]-azabicyclic system (R/S)-8 in 62% yield. The unsubstituted double bond was selectively reduced using Wilkinson catalyst to provide N-protected anhydroecgonine methyl ester ((R/S)-4). Following deprotection of N8 nitrogen with TBAF and reductive methylation with formaldehyde and sodium cyanoborohydride, (R/S)-5 was obtained in overall good yield.
See also
References
- ↑ Scheidweiler KB, Plessinger MA, Shojaie J, Wood RW, Kwong TC. Pharmacokinetics and pharmacodynamics of methylecgonidine, a crack cocaine pyrolyzate. Journal of Pharmacology and Experimental Therapeutics. 2003 Dec;307(3):1179-87.
- ↑ Pharmacokinetics and Pharmacodynamics of Methylecgonidine, a Crack Cocaine Pyrolyzate - Scheidweiler et al. 307 (3): 1179 Figure IG6 - Journal of Pharmacology And Experimental Therapeutics
- ↑ British Journal of Pharmacology - Abstract of article: Evidence for cocaine and methylecgonidine stimulation of M2 muscarinic receptors in cultured human embryonic lung cells
- ↑ Studies on Hydrolytic and Oxidative Metabolic Pathways of Anhydroecgonine Methyl Ester (Methylecgonidine) Using Microsomal Preparations from Rat Organs (Chemical Research in Toxicology/ACS Publications)
- ↑ Lua error in package.lua at line 80: module 'strict' not found.
- ↑ DeJong, A. W. K. Recl. Trav. Chim. 1937, 57, 186.
- ↑ Matchett, J. R.; Levine, J. J. Am. Chem. Soc. 1941, 63, 2444.
- ↑ Bell, M. R.; Archer, S. J. Am. Chem. Soc. 1960, 82, 4642.
- ↑ Kline, R. H., Jr.; Wright, J.; Fox, K. M.; Eldefrawi, M. E. J. Med.Chem. 1990, 33, 2024.
- ↑ http://www.chemsynthesis.com/base/chemical-structure-15475.html
- ↑ Lua error in package.lua at line 80: module 'strict' not found.
- ↑ Davies, H. M. L.; Saikali, E.; Young, W. B. J. Org. Chem. 1991, 56, 5696.
- ↑ Davies, H. M. L.; Young, W. B.; Smith, H. D. Tetrahedron Lett.1989, 30, 4653.